Group A Streptococcus (GAS) invasive disease is characterized by the dissemination of bacteria from the skin surface or a superficial wound through the epithelial barrier, in a paracellular fashion, into underlying tissues. The incidence of invasive GAS disseminated infection is increased by approximately 50-fold in children with primary varicella zoster virus (VZV) infection (chickenpox). The association of GAS invasive infection with VZV and not with other skin-damaging disorders suggests that VZV infection results in specific changes in the skin that enhance susceptibility to GAS infection. The focus of this application is the hypothesis that VZV infection of the epidermis induces expression of the GAS receptor CD44, enhanced GAS binding to epithelial cells, and augments CD44-mediated cytoskeletal rearrangements leading to intercellular junction disruption. GAS binding to CD44 triggers a cell signaling cascade that results in disruption of cell-cell junctions, thereby facilitating the paracellular translocation of GAS and culminating in invasive disease. The specific aims of the application are: (1) to determine the effect of VZV on GAS association with keratinocytes; (2) to characterize the cytoskeletal changes induced by VZV infection of polarized keratinocytes and the effects on the GAS-CD44 mediated cytoskeletal activity; and (3) to define the effects of VZV infection on intercellular junction integrity, epithelial barrier function, and GAS translocation. By comparing uninfected, VZV-infected, and VZV- and GAS-co-infected polarized keratinocyte monolayers, these studies will systematically evaluate the specific cellular responses elicited by VZV and the mechanisms that impact on pathogenesis of invasive GAS infection. These results will advance our understanding of the intracellular cytoskeletal changes induced by VZV that lead to disruption of the epithelial barrier and may provide insight into the mechanisms of opportunistic co-infection by GAS. Ultimately results of this line of investigation may suggest strategies to limit bacterial complications of this and other viral infections.